p16 immune cell - controlled disease tolerance as a broad defense and healthspan extending strategy.

The ability of an organism to overcome infectious diseases has traditionally been linked to killing invading pathogens. Accumulating evidence, however, indicates that, apart from restricting pathogen loads, organismal survival is coupled to an additional yet poorly understood mechanism called disease tolerance. Here we report that p16 immune cells play a key role in establishing disease tolerance. We found that the FDA-approved BNT162b2 mRNA COVID-19 vaccine is a potent and rapid inducer of p16 immune subsets both in mice and humans. In turn, p16 immune cells were indispensable for counteracting different lethal conditions, including LPS-induced sepsis, acute SARS-CoV-2 infection and ionizing irradiation. Mechanistically, we propose that activation of TLR7 or a low physiological activity of STING is sufficient to induce p16 immune subset that, in turn, establishes a low adenosine environment and disease tolerance. Furthermore, containing these signals within a beneficial range by deleting MDA5 that appeared sufficient to maintain a low activity of STING, induces p16 immune cells and delays organ deterioration upon aging with improved healthspan. Our data highlight the beneficial role of p16 immune subsets in establishing a low adenosine environment and disease tolerance.